Pegylated and fatty acid grafted chitosan oligosaccharide, synthesis method and application for drug delivery system

Abstract

The present invention provides a PEGylated and fatty acid grafted chitosan oligosaccharide comprising a structural unit represented by the following Formula (I) and a structural unit represented by the following Formula (II) and synthesize method, wherein the chitosan oligosaccharide has a molecular weight of less than 200,000 Da, and a degree of deacetylation of 70%-100%, and part of free amino groups of chitosan oligosaccharide chain are replaced by a fatty acid or PEG, where n refers to degree of polymerization of the PEG, and R is an alkyl group having 11-21 carbon atoms. The grafting ratio of fatty acids is 1%-50%, and the grafting ratio of PEG is 0.05%-50%. The present invention also comprise a pharmaceutical composition comprising the PEGylated and fatty acid grafted chitosan oligosaccharide as a carrier, and use of the PEGylated and fatty acid grafted chitosan oligosaccharide in preparation of a pharmaceutical composition.

The invention claimed is: 
     
       1. A PEGylated and fatty acid grafted chitosan oligosaccharide comprising a structural unit represented by the following Formula (I) and a structural unit represented by the following Formula (II), 
       
         
           
           
               
               
           
         
         wherein part of free amino groups of chitosan oligosaccharide chain are replaced by a fatty acid having 12-22 carbon atoms or a PEG having a molecular weight of 1,000-10,000 Da, where n refers to degree of polymerization of the PEG, and R is an alkyl group having 11-21 carbon atoms; and 
         the grafting ratio of fatty acids is 1%-50%, and the grafting ratio of the PEG is 0.05%-50%. 
       
     
     
       2. The PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1 , wherein the grafting ratio of the PEG is 0.5%-50%. 
     
     
       3. The PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1  or  2 , wherein the grafting ratio of fatty acids is 5%-50%. 
     
     
       4. The PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1 , wherein the PEG has a molecular weight of 2,000-10,000 Da. 
     
     
       5. The PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1 , wherein the fatty acid is at least one selected from the group consisting of lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid and docosanoic acid. 
     
     
       6. A method for preparing the PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1 , comprising the following steps:
 (a) degrading a chitosan in the presence of an enzyme to obtain a chitosan oligosaccharide having a molecular weight of less than 200,000 Da; 
 (b) coupling the chitosan oligosaccharide with a fatty acid having 12-22 carbon atoms in the presence of a crosslinking coupling agent to obtain a fatty acid grafted chitosan oligosaccharide; and 
 (c) coupling a terminal-substituted PEG with the fatty acid grafted chitosan oligosaccharide to obtain the PEGylated and fatty acid grafted chitosan oligosaccharide, wherein the molecular weight of the PEG is 1,000-10,000 Da. 
 
     
     
       7. The method according to  claim 6 , wherein in the steps (c), the molar ratio of the terminal-substituted PEG to the fatty acid grafted chitosan oligosaccharide is 1:20-80:1. 
     
     
       8. The method according to  claim 6 , wherein the terminal-substituted PEG is selected from the group consisting of terminal-aldehydated PEG, terminal-carboxylated PEG, terminal-succinimidated PEG and terminal-maleic anhydridated PEG. 
     
     
       9. A pharmaceutical composition comprising a pharmaceutically active ingredient and the PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1 . 
     
     
       10. The pharmaceutical composition according to  claim 9 , wherein the pharmaceutically active ingredient is an antitumor drug. 
     
     
       11. The pharmaceutical composition according to  claim 10 , which is capable to of reversing drug resistance of tumor cells. 
     
     
       12. The pharmaceutical composition according to  claim 9 , wherein the pharmaceutically active ingredient is a gene therapy drug. 
     
     
       13. The pharmaceutical composition according to  claim 9 , wherein the pharmaceutically active ingredient is an antiviral drug. 
     
     
       14. The pharmaceutical composition according to  claim 13 , wherein the anti-hepatitis B virus drug is at least one selected from the group consisting of adefovir, acyclovir, adefovir dipivoxil, entecavir and ganciclovir. 
     
     
       15. A method of preparing a pharmaceutical composition comprising a step of combining the PEGylated and fatty acid grafted chitosan oligosaccharide according to  claim 1  with a pharmaceutically active ingredient. 
     
     
       16. The method according to  claim 15 , wherein the pharmaceutical composition comprises an antitumor drug, a gene therapy drug or an antiviral drug. 
     
     
       17. The pharmaceutical composition according to  claim 10 , wherein the anititumor drug is at least one selected from the group consisting of mitomycin C, doxorubicin, paclitaxel and hydroxycamptothecin. 
     
     
       18. The pharmaceutical composition according to  claim 12 , wherein the gene therapy drug is plasmid DNA or siRNA. 
     
     
       19. The pharmaceutical composition according to  claim 13 , wherein the antiviral drug is an anti-hepatitis B virus drug.